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Session 107-Poster Abstracts
Resistance to Integrase Inhibitors
Friday, 2-4 pm; Poster Hall
Paper # 554    
Resistance-associated Mutations to Integrase Inhibitor S/GSK1349572 in HIV-1 Integrase Inhibitor-naive and Raltegravir-experienced Patients
Anne-Genevieve Marcelin*1, I Malet1, L Fabeni2, D Armenia2, S Fourati1, B Masquelier3, C Katlama1, C F Perno2, V Calvez1, and F Ceccherini-Silberstein2
1INSERM U943, Hosp Pitie-Salpetriere, Univ Pierre et Marie Curie, Paris, France; 2Univ of Rome Tor Vergata, Italy; and 3Hosp Bordeaux, France

 

 

Background:  S/GSK1349572 is a next generation HIV-1 strand transfer integrase inhibitor (INI) with high potency and putative activity on viruses resistant to first generation INI. Little is known about the resistance profile of S/GSK1349572: In vitro serial passage experiments identified 5 single or combined amino acid substitutions in the integrase gene that are involved in the development of resistance to S/GSK1349572 (T124A, T124A/S153F, S153Y, T124A/S153Y, and L101I/T124A/S153Y). The aim of this study was to determine the prevalence of resistance mutations to S/GSK1349572 in INI-naive and INI-experienced patients.

Methods:  The sequences of the entire integrase gene from 466 INI-naive patients infected with subtype B HIV-1 strains and 84 INI-experienced (raltegravir-failing) patients infected with subtype B were analyzed for the presence of previously described in vitro mutations linked to resistance to S/GSK1349572. INI-experienced patients were raltegravir (RAL)-failing patients with an integrase genotypic test at failure after RAL starting regimen with a contextual HIV RNA value >50 copies/mL.

Results:  The mutations L101I, T124A, and the double mutant L101I/T124A can be present in INI-naive patients with frequencies of 45.3%, 28.1%, and 10.9%, respectively. In INI-experienced patients failing to RAL, frequencies of L101I, T124A and L101I/T124A were 57.1%, 35.7% and 20.2%, respectively. Thus, mutations L101I and the double mutant L101I/T124A were statistically more frequent in RAL-failing patients than in INI-naive patients with P-values =0.04 and 0.02, respectively. Neither the mutation S153Y nor the profiles T124A/S153F, T124A/S153Y, and L101I/T124A/S153Y were identified in the sequences from INI naive or experienced patients studied.

Conclusions:  Some of the mutations selected by in vitro passages with S/GSK1349572 are more frequent in patients failing RAL than in INI-naive patients. Thus, the impact on virological response of L101I and T124A mutations alone and the double mutant L101I/T124A should be further addressed in vivo in both INI-naive patients and particularly in RAL-failing patients treated with S/GSK1349572.